Derivatives of sobetirome

ABSTRACT

Disclosed are halo substituted derivative compounds of sobetirome with improved pharmacological characteristics relative to sobetirome, pharmaceutical compositions that include those compounds and methods of treating diseases such as neurodegenerative disorders using those pharmaceutical compositions.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application is a continuation of a U.S. application Ser. No.16/301,711 filed on Nov. 14, 2018, which is the National stage ofInternational Application No. PCT/US2017/03338 filed on May 18, 2017 andwhich claims priority to U.S. Provisional Pat. Appl. No. 62/338,178,filed on May 18, 2016, which applications are incorporated herein byreference in their entirety.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

This invention was made with government support under grant numberDK-52798 awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

BACKGROUND OF THE INVENTION

Thyroid hormone (TH) is a key signal for oligodendrocyte differentiationand myelin formation during development and also stimulatesremyelination in adult models of multiple sclerosis (MS) (Calzà. L etal. Brain Res Revs 48, 339-346 (2005); incorporated by referenceherein.) However, TH is not an acceptable long-term therapy due to therebeing virtually no therapeutic window in which remyelination can beachieved while avoiding the cardiotoxicity and bone demineralizationassociated with chronic hyperthyroidism. Some thyroid hormone analogscan activate thyroid hormone-responsive genes while avoiding theassociated downsides of TH by exploiting molecular and physiologicalfeatures of thyroid hormone receptors (Maim J et al. Mini Rev Med Chem7, 79-86 (2007); incorporated by reference herein). These receptors areexpressed in two major forms with heterogenous tissue distributions andoverlapping but distinct sets of target genes (Yen P M, Physiol Rev 81,1097-1142 (2001); incorporated by reference herein). TRα is enriched inthe heart, brain, and bone while TRβ is enriched in the liver (O'Shea PJ et al. Nucl Recept Signal 4, e011 (2006); incorporated by referenceherein). Developing selective thyromimetics has been challenging due tothe high sequence homology of thyroid hormone receptor subtypes—only oneamino acid residue on the internal surface of the ligand binding domaincavity varies between the al and (31 forms. GC-1 was one of the firstpotent analogs that demonstrated significant TRβ-selectivity in vitro(Chiellini G et al. Chem Biol 5, 299-306 (1998) and Yoshihara H A I etal. J Med Chem 46, 3152-3161 (2003); both of which are incorporated byreference herein) and in vivo (Trost S U et al. Endocrinology 141,3057-3064 (2000); Grover G J et al. Endocrinology 145, 1656-1661 (2004);and Baxter J D et al. Trends Endocrinol Metab 15, 154-157 (2004); all ofwhich are incorporated by reference herein).

BRIEF SUMMARY OF THE INVENTION

Disclosed herein are compounds according to Formula I:

-   -   or any pharmaceutically acceptable salt thereof, wherein:    -   R¹ and R² are independently selected from the group consisting        of fluoro, chloro, bromo, and iodo, and    -   R³ is independently selected from the group consisting of —OH        and —NR^(3a)R^(3b),    -   R^(3a) is independently selected from the group consisting of        hydrogen and C₁₋₆ alkyl, and    -   R^(3b) is C₁₋₆ alkyl.

Also disclosed are pharmaceutical compositions comprising an effectiveamount of the disclosed compounds or a pharmaceutically acceptable saltthereof and one or more pharmaceutically acceptable carriers. In someexamples, the pharmaceutical composition is for use in treating aneurodegenerative disorder including neurodegenerative disordersclassified as a demyelinating disease such as X-linkedadrenoleukodystrophy or multiple sclerosis.

Also disclosed are methods of treating a neurodegenerative disorder in asubject, such methods involve administering the disclosed pharmaceuticalcompositions to the subject, thereby treating the neurodegenerativedisorder. In some aspects, the neurodegenerative disorder can beclassified as a demyelinating disease such as X-linkedadrenoleukodystrophy or multiple sclerosis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a plot of the data from a TRE-driven dual luciferasetransactivation assays with calculated sigmoidal dose-response curvesagainst hTRα1 in transiently transfected HEK293 cells. Plots show meansof triplicates with error bars normalized to T3 response.

FIG. 1B is a plot of the data from a TRE-driven dual luciferasetransactivation assays with calculated sigmoidal dose-response curvesagainst hTRβ1 in transiently transfected HEK293 cells. Plots show meansof triplicates with error bars normalized to T3 response.

FIG. 2 is a set of three bar graphs showing in vivo concentrations ofGC-1, JD-20, and JD-21 in C57/B mouse tissues 1 hr after systemicadministration (ip) of GC-1, JD-20, and JD-21 9.14 μmol/kg dosesmeasured by LC-MS/MS in brain and serum.

FIG. 3 is a bar graph showing expression of TR regulated gene Hairless(Hr) mRNA normalized to glyceraldehyde 3-phosphate dehydrogenase (GAPDH)mRNA measured by qPCR in C57/B mouse brain (3 mice/dose) 2 hr aftersystemic administration (ip) of saturating doses of T3 (0.305 μmol/kg)or GC-1 (9.14 μmol/kg) plus escalating doses of JD-20 and JD-21 (0.914and 9.14 μmol/kg).

FIG. 4 is a plot of the expression of TR regulated gene Hairless (Hr)mRNA normalized to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNAmeasured by qPCR in C57/B mouse brain (3 mice/dose) 2 hr after systemicadministration (ip) of GC-1, JD-20, and JD-21.

FIG. 5A is a plot of drug concentration the brain of C57Bl/6 micefollowing systemic administration.

FIG. 5B is a plot of drug concentration in the serum of C57Bl/6 micefollowing systemic administration.

FIG. 5C shows the ratio brain concentration to serum concentration ofdrugs in C57Bl/6 mice following systemic administration.

FIG. 6A is a plot of drug concentration in the brain of C57Bl/6 micefollowing oral administration.

FIG. 6B is a plot of drug concentration in serum if C57Bl/6 micefollowing oral administration.

FIG. 6C shows the ratio brain concentration to serum concentration ofdrugs in C57Bl/6 mice following oral administration.

FIG. 7A shows a plot of JD-20 concentration in the brain over a 24 htime-course study following oral administration of the compound to mice.

FIG. 7B shows a plot of JD-20 concentrations in the serum over a 24 htime-course study following oral administration of the compound to mice.

FIG. 8 shows the induction of Hr gene expression by JD-20, MA-JD20,JD-21, and MA-JD21 following oral administration of the compounds tomice.

FIG. 9 shows that MA-JD20 and MA-JD21 are substrates for fatty-acidamide hydrolase (FAAH).

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

Unless specifically defined otherwise, the technical terms, as usedherein, have their normal meaning as understood in the art. Thefollowing explanations of terms and methods are provided to betterdescribe the present compounds, compositions and methods, and to guidethose of ordinary skill in the art in the practice of the presentdisclosure. It is also to be understood that the terminology used in thedisclosure is for the purpose of describing particular embodiments andexamples only and is not intended to be limiting.

As used herein, the singular terms “a,” “an,” and “the” include pluralreferents unless context clearly indicates otherwise. Similarly, theword “or” is intended to include “and” unless the context clearlyindicates otherwise. Also, as used herein, the term “comprises” means“includes.” Hence “comprising A or B” means including A, B, or A and B.

Variables such as R, including all subvariables thereof (such as R¹, R²,etc.) used throughout the disclosure are the same variables aspreviously defined unless stated to the contrary.

As used herein, the term “alkyl,” by itself or as part of anothersubstituent, refers to a straight or branched, saturated, aliphaticradical having the number of carbon atoms indicated. Alkyl can includeany number of carbons, such as C₁₋₂, C₁₋₃, C₁₋₄, C₁₋₅, C₁₋₆, C₁₋₇, C₁₋₈,C₁₋₉, C₁₋₁₀, C₂₋₃, C₂₋₄, C₂₋₅, C₂₋₆, C₃₋₄, C₃₋₅, C₃₋₆, C₄₋₅, C₄₋₆ andC₅₋₆. For example, C₁₋₆ alkyl includes, but is not limited to, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, hexyl, etc. Alkyl can also refer to alkyl groupshaving up to 20 carbons atoms, such as, but not limited to heptyl,octyl, nonyl, decyl, etc.

As used herein, the terms “acute disseminated encephalomyelitis” and“ADEM” refer to an immune-mediated demyelinating disease of the centralnervous system. ADEM usually occurs following a viral infection, but mayalso appear following vaccination or following bacterial or parasiticinfection. In some cases, ADEM develops spontaneously. The diseaseinvolves autoimmune demyelination, similar to multiple sclerosis, and istherefore considered a multiple sclerosis borderline disease. ADEMproduces multiple inflammatory lesions in the brain and spinal cord,particularly in the white matter. The lesions are typically found in thesubcortical and central white matter and cortical gray-white junction ofboth cerebral hemispheres, cerebellum, brainstem, and spinal cord, butperiventricular white matter and gray matter of the cortex, thalami andbasal ganglia may also be involved. When a patient suffers more than onedemyelinating episode, the disease is referred to as recurrentdisseminated encephalomyelitis or multiphasic disseminatedencephalomyelitis.

As used herein, the terms “acute hemorrhagic leukoencephalitis,” “AHL,”and “AHLE” refer to a hyperacute and frequently fatal form of ADEM. Thisdisease is also known as acute necrotizing encephalopathy (ANE), acutehemorrhagic encephalomyelitis (AHEM), acute necrotizing hemorrhagicleukoencephalitis (ANHLE), Weston-Hurst syndrome, or Hurst's disease.

As used herein, the term “administration” refers to providing acompound, a prodrug of a compound, or a pharmaceutical compositioncomprising a compound or prodrug as described herein. The compound orcomposition can be administered by another person to the subject or itcan be self-administered by the subject.

As used herein, the term “adult Refsum disease” refers to an autosomalrecessive neurological disease that is associated with theover-accumulation of phytanic acid in cells and tissues. Adult Refsumdisease is divided into the adult Refsum disease 1 and adult Refsumdisease 2 subtypes. Individuals with Refsum disease present withneurologic damage, cerebellar degeneration, and peripheral neuropathy.Onset is most commonly in childhood/adolescence with a progressivecourse, although periods of stagnation or remission occur. Symptoms alsoinclude ataxia, scaly skin (ichthyosis), difficulty hearing, and eyeproblems including cataracts and night blindness.

As used herein, the term “Alexander disease” refers to a very rare,congenital demyelinating disease. The disease primarily affects infantsand children, causing developmental delay and changes in physicalcharacteristics. Alexander disease is a type of leukodystrophy.

As used herein, the term “Alzheimer's disease” refers to the most commonform of dementia. Symptoms of Alzheimer's disease include memory loss,confusion, irritability, aggression, mood swings and trouble withlanguage. This disease is characterized by the loss of neurons andsynapses in the cerebral cortex and certain subcortical regions. Theloss results in gross atrophy of the affected regions, includingdegeneration in the temporal lobe, and parts of the frontal cortex andcingulate gyrus. Amyloid plaques and neurofibrillary tangles are visibleby microscopy in brains of those afflicted with this disease. The causeof Alzheimer's disease is unknown; however, several hypotheses exist,including that the disease is caused by age-related myelin breakdown inthe brain.

As used herein, the term “Balo concentric sclerosis” refers to ademyelinating disease similar to standard multiple sclerosis, but withthe particularity that the demyelinated tissues form concentric layers.Patients with this disease can survive and/or have spontaneousremission. Typically, the clinical course is primary progressive, but arelapsing-remitting course has been reported.

As used herein, the term “Canavan disease” refers to an autosomalrecessive degenerative disorder that causes progressive damage to nervecells in the brain. Canavan disease is a leukodystrophy and is one ofthe most common degenerative cerebral diseases of infancy. This diseaseis also called Canavan-Van Bogaert-Bertrand disease, aspartoacylasedeficiency and aminoacylase 2 deficiency.

As used herein, the terms “Central pontine myelinolysis” and “CPM” referto a neurologic disease caused by severe damage of the myelin sheath ofnerve cells in the brainstem, more precisely in the area termed thepons. The most common cause is the rapid correction of low blood sodiumlevels (hyponatremia). Frequently observed symptoms in this disorder aresudden para or quadraparesis, dysphagia, dysarthria, diplopia and lossof consciousness. The patient may experience locked-in syndrome wherecognitive function is intact, but all muscles are paralyzed with theexception of eye blinking.

As used herein, the term “cerebral palsy” refers to a group ofpermanent, non-progressive movement disorders that cause physicaldisability. Cerebral palsy is caused by damage to the motor controlcenters of the developing brain and can occur during pregnancy, duringchildbirth, or after birth up to about age three. Patients with cerebralpalsy exhibit damage to myelin sheaths.

As used herein, the term “cerebrotendineous xanthomatosis” refers to aninherited disorder associated with the deposition of a form ofcholesterol (cholestanol) in the brain and other tissues and withelevated levels of cholesterol in plasma but with normal totalcholesterol level. It is characterized by progressive cerebellar ataxiabeginning after puberty and by juvenile cataracts, juvenile or infantileonset chronic diarrhea, childhood neurological deficit, and tendineousor tuberous xanthomas. This disorder is an autosomal recessive form ofxanthomatosis. It falls within a group of genetic disorders called theleukodystrophies.

As used herein, the terms “chronic inflammatory demyelinatingpolyneuropathy” and “CIDP” refer to an acquired immune-mediatedinflammatory disorder of the peripheral nervous system. The disorder issometimes called chronic relapsing polyneuropathy (CRP) or chronicinflammatory demyelinating polyradiculoneuropathy (because it involvesthe nerve roots). CIDP is closely related to Guillain-Barré syndrome andit is considered the chronic counterpart of that acute disease. Itssymptoms are also similar to progressive inflammatory neuropathy. Anasymmetrical variant of CIDP is known as Lewis-Sumner syndrome. Thepathologic hallmark of the disease is loss of the myelin sheath.

As used herein, the term “demyelinating disease” refers to any diseaseof the nervous system in which myelin is damaged or lost, or in whichthe growth or development of the myelin sheath is impaired.Demyelination inhibits the conduction of signals in the affected nerves,causing impairment in sensation, movement, cognition, or other functionsfor which nerves are involved. Demyelinating diseases have a number ofdifferent causes and can be hereditary or acquired. In some cases, ademyelinating disease is caused by an infectious agent, an autoimmuneresponse, a toxic agent or traumatic injury. In other cases, the causeof the demyelinating disease is unknown (“idiopathic”) or develops froma combination of factors.

As used herein, the term “derivative” refers to a compound or portion ofa compound that is derived from or is theoretically derivable from aparent compound.

As used herein, the term “Devic's syndrome” refers to an autoimmune,inflammatory disorder in which a person's immune system attacks theoptic nerves and spinal cord, which results in inflammation of the opticnerve (optic neuritis) and the spinal cord (myelitis). Spinal cordlesions lead to varying degrees of weakness or paralysis in the legs orarms, loss of sensation, and/or bladder and bowel dysfunction. Althoughinflammation may also affect the brain, the lesions are different fromthose observed in MS. Devic's syndrome is similar to MS in that thebody's immune system attacks the myelin surrounding nerve cells. Unlikestandard MS, the attacks are not believed to be mediated by the immunesystem's T cells but rather by antibodies called NMO-IgG. Theseantibodies target a protein called aquaporin 4 in the cell membranes ofastrocytes which acts as a channel for the transport of water across thecell membrane. Devic's syndrome is also known as Devic's syndrome orneuromyelitis optica (NMO).

As used herein, the term “diffuse myelinoclastic sclerosis” refers to anuncommon neurodegenerative disease that presents clinically aspseudotumoral demyelinating lesions. It usually begins in childhood,affecting children between 5 and 14 years old; however, cases in adultsare possible. This disease is considered one of the borderline forms ofMS and is sometimes referred to as Schilder's disease.

As used herein, the term “effective amount” refers to a quantity of aspecified agent sufficient to achieve a desired effect in a subjectbeing treated with that agent. Ideally, an effective amount of an agentis an amount sufficient to inhibit or treat the disease without causingsubstantial toxicity in the subject. The effective amount of an agentwill be dependent on the subject being treated, the severity of theaffliction, and the manner of administration of the pharmaceuticalcomposition. Methods of determining an effective amount of the disclosedcompound sufficient to achieve a desired effect in a subject will beunderstood by those of skill in the art in light of this disclosure.

As used herein, the term “encephalomyelitis” refers to inflammation ofthe brain and spinal cord.

As used herein, the terms “experimental autoimmune encephalomyelitis”and “EAE” refer to an animal model of MS (for example, see Gold et al.Brain 129, 1953-1971 (2006). EAE animals exhibit characteristic plaquesof tissue injury disseminated throughout the central nervous system.Plaques show infiltration of nervous tissue by lymphocytes, plasmacells, and macrophages, which cause destruction of the myelin sheathsthat surround nerve cell axons in the brain and spinal cord. In somecases, EAE is induced by immunization of susceptible animals, such asmice, rats, guinea pigs, or non-human primates, with either myelin orvarious components of myelin. For example, EAE can be induced byimmunization with components of the myelin sheath, such as myelin basicprotein, proteolipid protein, or myelin oligodendrocyte glycoprotein(MOG). EAE is a useful and widely accepted model for studying mechanismsof autoimmune CNS tissue injury and for testing potential therapies forMS. EAE also includes “passive EAE” which is induced in the same mannerin donor animals, but involves the transfer of activated T-cellsharvested from the donor animal's lymph nodes to naïve recipientanimals.

As used herein, the term “Guillain-Barré syndrome” refers to an acutepolyneuropathy, a disorder affecting the peripheral nervous system.Ascending paralysis, weakness beginning in the feet and hands andmigrating towards the trunk, is the most typical symptom, and somesubtypes cause change in sensation or pain, as well as dysfunction ofthe autonomic nervous system. It can cause life-threateningcomplications, in particular if the respiratory muscles are affected orif the autonomic nervous system is involved. This disease is usuallytriggered by an infection. Acute inflammatory demyelinatingpolyneuropathy (AIDP) is the most common subtype of this disease. Othersubtypes of Guillain-Barré syndrome include Miller Fischer syndrome,acute motor axonal neuropathy (Chinese paralytic syndrome), acute motorsensory axonal neuropathy, acute panautonomic neuropathy, andBickerstaff's brainstem encephalitis.

As used herein, the term “hemorrhage” refers to bleeding or escape ofblood from a vessel.

As used herein, the term “hypoxia” refers to the lack of oxygen supplyto the tissues of the body below the normal level.

As used herein, the terms “idiopathic inflammatory demyelinatingdisease” and “IIDD” refer to a broad spectrum of central nervous systemdisorders that can usually be differentiated on the basis of clinical,imaging, laboratory and pathological findings. Idiopathic inflammatorydemyelinating diseases are sometimes known as borderline forms ofmultiple sclerosis. IIDD generally refers to a collection of multiplesclerosis variant diseases, including but not limited to, optic-spinalMS, Devic's disease, ADEM, acute hemorrhagic leukoencephalitis, Baloconcentric sclerosis, Schilder disease, Marburg multiple sclerosis,tumefactive multiple sclerosis and solitary sclerosis.

As used herein, the term “infantile Refsum disease” refers to aperoxisome biogenesis disorder associated with deficiencies in thecatabolism of very long chain fatty acids and branched chain fatty acids(such as phytanic acid) and plasmalogen biosynthesis. Infantile Refsumdisease is a rare, autosomal recessive congenital disorder, and one ofthree peroxisome biogenesis disorders that belong to the Zellwegerspectrum of peroxisome biogenesis disorders.

As used herein, the term “injury” refers to any type of physical damageto cells, tissues, or the body. In some cases, nervous system (e.g., CNSor PNS) injury results in demyelination and/or a demyelinating disease.

As used herein, the term “ischemia” refers to a vascular phenomenon inwhich a decrease in the blood supply to a bodily organ, tissue, or partis caused, for instance, by constriction or obstruction of one or moreblood vessels. Ischemia sometimes results from vasoconstriction,thrombosis or embolism. Ischemia can lead to direct ischemic injury,tissue damage due to cell death caused by reduced oxygen supply. In somecases, ischemia can lead to demyelination.

As used herein, the term “Krabbe disease” refers to a rare, often fataldegenerative disorder that affects the myelin sheath of the nervoussystem. It is a form of sphingolipidosis, as it involves dysfunctionalmetabolism of sphingolipids. This condition is inherited in an autosomalrecessive pattern. Krabbe disease is also known as globoid cellleukodystrophy or galactosylceramide lipidosis.

As used herein, the term “Leber hereditary optic neuropathy” refers to amitochondrially inherited (transmitted from mother to offspring)degeneration of retinal ganglion cells (RGCs) and their axons that leadsto an acute or subacute loss of central vision; this affectspredominantly young adult males.

As used herein, the term “leukodystrophy” refers to a group of diseasesthat affects the growth or development of the myelin sheath.

As used herein, the term “leukoencephalopathy” refers to any of a groupof diseases affecting the white substance of the brain; can referspecifically to several diseases including, for example,“leukoencephalopathy with vanishing white matter” and “toxicleukoencephalopathy.” Leukoencephalopathies are leukodystrophy-likediseases.

As used herein, the term “Marburg multiple sclerosis” refers to acondition in which the central nervous system has multiple demyelinatinglesions with atypical characteristics for those of standard multiplesclerosis. This disease is a borderline form of multiple sclerosis andis also known as tumefactive multiple sclerosis or fulminant multiplesclerosis. It is called tumefactive because the lesions are “tumor-like”and they mimic tumors clinically, radiologically and sometimespathologically.

As used herein, the term “Marchiafava-Bignami disease” refers to aprogressive neurological disease characterized by corpus callosumdemyelination and necrosis and subsequent atrophy. It is classicallyassociated with chronic alcoholics.

As used herein, the terms “metachromatic leukodystrophy” and “MLD” referto a lysosomal storage disease that is commonly listed in the family ofleukodystrophies, as well as in the sphingolipidoses as it affects themetabolism of sphingolipids. MLD is directly caused by a deficiency ofthe enzyme arylsulfatase A.

As used herein, the terms “multifocal motor neuropathy” and “MMN” referto a progressively worsening condition where muscles in the extremitiesgradually weaken. This disorder, a motor neuropathy syndrome, issometimes mistaken for amyotrophic lateral sclerosis (ALS) because ofthe similarity in the clinical picture, especially if musclefasciculations are present. MMN is usually asymmetric and is thought tobe autoimmune.

As used herein, the terms “multiple sclerosis” and “MS” refer to aslowly progressive CNS disease characterized by disseminated patches ofdemyelination in the brain and spinal cord, resulting in multiple andvaried neurological symptoms and signs, usually with remissions andexacerbation. The cause of MS is unknown but an immunologicalabnormality is suspected. An increased family incidence suggests geneticsusceptibility, and women are somewhat more often affected than men. Thesymptoms of MS include weakness, lack of coordination, paresthesias,speech disturbances, and visual disturbances, most commonly doublevision. More specific signs and symptoms depend on the location of thelesions and the severity and destructiveness of the inflammatory andsclerotic processes. Relapsing-remitting multiple sclerosis (RRMS) is aclinical course of MS that is characterized by clearly defined, acuteattacks with full or partial recovery and no disease progression betweenattacks. Secondary-progressive multiple sclerosis (SPMS) is a clinicalcourse of MS that initially is relapsing-remitting, and then becomesprogressive at a variable rate, possibly with an occasional relapse andminor remission. Primary-progressive multiple sclerosis (PPMS) presentsinitially in the progressive form. A clinically isolated syndrome is thefirst neurologic episode, which is caused by inflammation/demyelinationat one or more sites in the CNS. Progressive-relapsing multiplesclerosis (PRMS) is a rare form of MS (˜5%) characterized by a steadilyworsening disease state from onset, with acute relapses but noremissions.

As used herein, the term “myelin” refers to a lipid substance forming asheath (known as the myelin sheath) around the axons of certain nervefibers. Myelin is an electrical insulator that serves to speed theconduction of nerve impulses in nerve fibers. “Myelination” (also“myelinization”) refers to the development or formation of a myelinsheath around a nerve fiber. Similarly, “remyelination” (also,“remyelinization”) refers to the repair or reformation of the myelinsheath, such as following injury, exposure to a toxic agent, or aninflammatory response, or during the course of a demyelinating disease.

As used herein, the term “neurodegenerative disease” refers to any typeof disease that is characterized by the progressive deterioration of thenervous system.

As used herein, the term “neuropathy” refers to a functional disturbanceor pathological change in the peripheral nervous system. Axonalneuropathy refers to a disorder disrupting the normal functioning of theaxons.

As used herein, the term “paraproteinemic demyelinating polyneuropathy”refers to a type of peripheral neuropathy characterized by autoantibodies directed against myelin associated glycoproteins (MAG).Anti-MAG antibodies inhibit the production of myelin, thereby leading toneuropathy.

As used herein, the terms “Pelizaeus-Merzbacher disease” and “PMD” referto a rare central nervous system disorder in which coordination, motorabilities, and intellectual function are delayed to variable extents.The disease is one in a group of genetic disorders collectively known asleukodystrophies.

As used herein, the terms “peroneal muscular atrophy” and “PMA” refer toa genetically and clinically heterogeneous group of inherited disordersof the peripheral nervous system characterized by progressive loss ofmuscle tissue and touch sensation across various parts of the body. Thisdisease is also known as Charcot-Marie-Tooth disease (CMT),Charcot-Marie-Tooth neuropathy and hereditary motor and sensoryneuropathy (HMSN).

As used herein, the term “pharmaceutical composition” refers to acomposition containing one or more of the compounds described herein, ora pharmaceutically acceptable salt thereof, formulated with apharmaceutically acceptable carrier, which can also include otheradditives, and manufactured or sold with the approval of a governmentalregulatory agency as part of a therapeutic regimen for the treatment ofdisease in a mammal. Pharmaceutical compositions can be formulated, forexample, for oral administration in unit dosage form (e.g., a tablet,capsule, caplet, gelcap, or syrup); for topical administration (e.g., asa cream, gel, lotion, or ointment); for intravenous administration(e.g., as a sterile solution free of particulate emboli and in a solventsystem suitable for intravenous use); or in any other formulationdescribed herein.

As used herein, the term “pharmaceutically acceptable carrier” refers toany ingredient other than the disclosed compounds, or a pharmaceuticallyacceptable salt thereof (e.g., a carrier capable of suspending ordissolving the active compound) and having the properties of beingnontoxic and non-inflammatory in a patient. Excipients may include, forexample: antiadherents, antioxidants, binders, coatings, compressionaids, disintegrants, dyes (colors), emollients, emulsifiers, fillers(diluents), film formers or coatings, flavors, fragrances, glidants(flow enhancers), lubricants, preservatives, printing inks, sorbents,suspensing or dispersing agents, sweeteners, or waters of hydration.Exemplary excipients include, but are not limited to: butylatedhydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic),calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone,citric acid, crospovidone, cysteine, ethylcellulose, gelatin,hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose,magnesium stearate, maltitol, mannitol, methionine, methylcellulose,methyl paraben, microcrystalline cellulose, polyethylene glycol,polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben,retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch(corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide,vitamin A, vitamin E, vitamin C, and xylitol.

As used herein, the term “pharmaceutically acceptable salt” refers tosalts prepared by conventional methods. These include basic salts ofinorganic and organic acids, such as, without limitation, hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonicacid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid,tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid,maleic acid, salicylic acid, benzoic acid, phenylacetic acid, andmandelic acid. “Pharmaceutically acceptable salts” of the presentlydisclosed compounds also include those formed from cations such as,without limitation, sodium, potassium, aluminum, calcium, lithium,magnesium, zinc, and from bases such as ammonia, ethylenediamine,N-methyl-glutamine, lysine, arginine, ornithine, choline,N,N′-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine,N-benzylphenethylamine, diethylamine, piperazine,tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.These salts may be prepared by standard procedures, for example byreaction of the free acid with a suitable organic or inorganic base. Anychemical compound recited in this specification may alternatively beadministered as a pharmaceutically acceptable salt thereof.Pharmaceutically acceptable salts are also inclusive of the free acid,base, and zwitterionic forms of the disclosed compounds. Descriptions ofexemplary pharmaceutically acceptable salts can be found in Stahl andWermuth, Eds., Handbook of Pharmaceutical Salts; Properties, Selectionand Use, Wiley VCH (2008). When the compounds disclosed herein includean acidic group such as a carboxy group, then suitable pharmaceuticallyacceptable cation pairs for the carboxy group are well known to thoseskilled in the art and include, without limitation, alkaline, alkalineearth, ammonium, and quaternary ammonium cations. Such salts are knownto those of skill in the art. Similarly when the compounds disclosedherein include a basic group such as an amino group, then suitablepharmaceutically acceptable anion pairs for the basic group aresimilarly well known and include halide, hydroxide, perhalate, halite,hypohalite, sulfate, sulfite, phosphate, phosphite, nitrate, nitrite,and others known to those of skill in the art. For additional examplesof pharmacologically acceptable salts, see Berge et al. J. Pharm. Sci.66, 1 (1977).

As used herein, the terms “progressive multifocal leukoencephalopathy”and “PML” refer to rare and usually fatal viral disease that ischaracterized by progressive damage or inflammation of the white matterof the brain in multiple locations. PML occurs almost exclusively inpeople with severe immune deficiency. The cause of PML is a type ofpolyomavirus called the JC virus. The virus is widespread, with 86% ofthe general population presenting antibodies, but it usually remainslatent, causing disease only when the immune system has been severelyweakened. PML is a demyelinating disease, in which the myelin sheathcovering the axons of nerve cells is gradually destroyed, impairing thetransmission of nerve impulses. The disease may occur in subjects (e.g.,humans) with severe immune deficiency, such as transplant patients onimmunosuppressive medications or those receiving certain kinds ofmedications. For example, PML has been associated with administration ofrituximab (off-label use in the treatment of multiple sclerosis). Itaffects the white matter, which is mostly composed of axons from theoutermost parts of the brain (cortex). Symptoms include weakness orparalysis, vision loss, impaired speech, and cognitive deterioration.

As used herein, the term “sobetirome” refers to a syntheticdiarylmethane derivative that was investigated clinically as a potentialtherapeutic for hypercholesterolemia (see U.S. Pat. No. 5,883,294, whichis incorporated by reference herein). Other names for sobetirome foundin the literature and regulatory filings include QRX-431 and GC-1.Sobetirome is also referred to herein as compound 1.

As used herein, the term “subject” refers to an animal (e.g., a mammal,such as a human). A subject to be treated according to the methodsdescribed herein may be one who has been diagnosed with aneurodegenerative disease involving demyelination, insufficientmyelination, or underdevelopment of a myelin sheath, e.g., a subjectdiagnosed with multiple sclerosis or cerebral palsy, or one at risk ofdeveloping the condition. Diagnosis may be performed by any method ortechnique known in the art. One skilled in the art will understand thata subject to be treated according to the present disclosure may havebeen subjected to standard tests or may have been identified, withoutexamination, as one at risk due to the presence of one or more riskfactors associated with the disease or condition.

As used herein, the term “transverse myelitis” refers to a neurologicaldisorder caused by an inflammatory process of the grey and white matterof the spinal cord, leading to axonal demyelination. Demyelinationarises idiopathically following infections or vaccination, or due tomultiple sclerosis. Symptoms include weakness and numbness of the limbsas well as motor, sensory, and sphincter deficits. Severe back pain mayoccur in some patients at the onset of the disease.

As used herein, the term “treatment” refers to an intervention thatameliorates a sign or symptom of a disease or pathological condition. Asused herein, the terms “treatment”, “treat” and “treating,” withreference to a disease, pathological condition or symptom, also refersto any observable beneficial effect of the treatment. The beneficialeffect can be evidenced, for example, by a delayed onset of clinicalsymptoms of the disease in a susceptible subject, a reduction inseverity of some or all clinical symptoms of the disease, a slowerprogression of the disease, a reduction in the number of relapses of thedisease, an improvement in the overall health or well-being of thesubject, or by other parameters well known in the art that are specificto the particular disease. A prophylactic treatment is a treatmentadministered to a subject who does not exhibit signs of a disease orexhibits only early signs, for the purpose of decreasing the risk ofdeveloping pathology. A therapeutic treatment is a treatmentadministered to a subject after signs and symptoms of the disease havedeveloped.

As used herein, the terms “tropical spastic paraparesis” and “TSP” referto an infection of the spinal cord by human T-lymphotropic virusresulting in paraparesis, weakness of the legs. TSP is also known asHTLV associated myelopathy or chronic progressive myelopathy. As thename suggests, this disease is most common in tropical regions,including the Caribbean and Africa.

As used herein, the term “Van der Knaap disease” refers to a form ofhereditary CNS demyelinating disease. This disease is a type ofleukodystrophy and is also known as megalencephalic leukoencephalopathywith subcortical cysts (MLC).

As used herein, the terms “X-linked adrenoleukodystrophy,” “X-ALD,”“ALD,” and “X-linked ALD” refer to a rare, inherited metabolic disorderthat leads to progressive brain damage, mental deterioration, failure ofthe adrenal glands, muscle spasms, blindness and eventually death. ALDis one disease in a group of inherited disorders calledleukodystrophies. Adrenoleukodystrophy progressively damages myelin.X-linked ALD male patients may be divided into 7 phenotypes: childhoodcerebral (progressive neurodegenerative decline leading to a vegetativestate), adolescent (similar to childhood cerebral form but with a slowerprogression), adrenomyeloneuropathy (progressive neuropathy,paraparesis, may progress to cerebral involvement), adult cerebral(dementia, similar progression to childhood cerebral form),olivo-ponto-cerebellar (cerebral and brain stem involvement), Addisondisease (adrenal insufficiency), asymptomatic (no clinical presentation,subclinical adrenal insufficiency, or AMN phenotype). X-linked ALDfemale patients may be divided into 5 phenotypes: asymptomatic (noneurologic or adrenal involvement), mild myelopathy, moderate to severemyelopathy (similar to male AMN phenotype), cerebral (progressivedementia and decline), and adrenal (primary adrenal insufficiency).X-linked ALD patients may progress from one phenotype to another overthe course of their life. ALD is also known as Addison-Schilder diseaseor Siemerling-Creutzfeldt disease.

As used herein, the term “Zellweger syndrome” refers to a rarecongenital disorder, characterized by the reduction or absence offunctional peroxisomes in the cells of an individual. This disease isclassified as a leukodystrophy and is one of three peroxisome biogenesisdisorders that belong to the Zellweger spectrum of peroxisome biogenesisdisorders.

II. Sobetirome Derivatives

In a first aspect, the invention provides a compound according toFormula I:

-   -   or any pharmaceutically acceptable salt thereof, wherein:    -   R¹ and R² are independently selected from the group consisting        of fluoro, chloro, bromo, and iodo, and    -   R³ is independently selected from the group consisting of —OH        and —NR^(3a)R^(3b),    -   R^(3a) is independently selected from the group consisting of        hydrogen and C₁₋₆ alkyl, and    -   R^(3b) is C₁₋₆ alkyl.

In some embodiments, R¹ is fluoro and R² is selected from the groupconsisting of chloro, bromo, and iodo; or R¹ is chloro and R² isselected from the group consisting of fluoro, bromo, and iodo; or R¹ isbromo and R² is selected from the group consisting of fluoro, chloro,and iodo; or R¹ is iodo and R² is selected from the group consisting offluoro, chloro, and bromo.

In some embodiments, R² is fluoro and R¹ is selected from the groupconsisting of chloro, bromo, and iodo; or R² is chloro and R¹ isselected from the group consisting of fluoro, bromo, and iodo; or R² isbromo and R¹ is selected from the group consisting of fluoro, chloro,and iodo; or R² is iodo and R¹ is selected from the group consisting offluoro, chloro, and bromo.

In some embodiments, R³ is —OH, R¹ is fluoro, and R² is selected fromthe group consisting of chloro, bromo, and iodo; or R³ is —OH, R¹ ischloro, and R² is selected from the group consisting of fluoro, bromo,and iodo; or R³ is —OH, R¹ is bromo, and R² is selected from the groupconsisting of fluoro, chloro, and iodo; or R³ is —OH, R¹ is iodo, and R²is selected from the group consisting of fluoro, chloro, and bromo.

In some embodiments, R³ is —OH, R² is fluoro, and R¹ is selected fromthe group consisting of chloro, bromo, and iodo; or R³ is —OH, R² ischloro, and R¹ is selected from the group consisting of fluoro, bromo,and iodo; or R³ is —OH, R² is bromo, and R¹ is selected from the groupconsisting of fluoro, chloro, and iodo; or R³ is —OH, R² is iodo, and R¹is selected from the group consisting of fluoro, chloro, and bromo.

In some embodiments, R³ is —NHR^(3b), R¹ is fluoro, and R² is selectedfrom the group consisting of chloro, bromo, and iodo; or R³ is—NHR^(3b), R¹ is chloro, and R² is selected from the group consisting offluoro, bromo, and iodo; or R³ is —NHR^(3b), R¹ is bromo, and R² isselected from the group consisting of fluoro, chloro, and iodo; or R³ is—NHR^(3b), R¹ is iodo, and R² is selected from the group consisting offluoro, chloro, and bromo. In some such embodiments, R^(3b) is C₁₋₆alkyl. R^(3b) can be, for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, branched pentyl,n-hexyl, or branched hexyl. In some embodiments, R^(3b) is methyl.

In some embodiments, R³ is —NHR^(3b), R² is fluoro, and R¹ is selectedfrom the group consisting of chloro, bromo, and iodo; or R³ is—NHR^(3b), R² is chloro, and R¹ is selected from the group consisting offluoro, bromo, and iodo; or R³ is —NHR^(3b), R² is bromo, and R¹ isselected from the group consisting of fluoro, chloro, and iodo; or R³ is—NHR³b, R² is iodo, and R¹ is selected from the group consisting offluoro, chloro, and bromo. In some such embodiments, R^(3b) is C₁₋₆alkyl. R^(3b) can be, for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, branched pentyl,n-hexyl, or branched hexyl. In some embodiments, R^(3b) is methyl.

In some embodiments, R¹ and R² are independently selected from the groupconsisting of chloro and bromo.

In some embodiments, R¹ and R² are both bromo. In some embodiments, R¹and R² are both bromo, and R³ is —OH.

In some embodiment, R¹ and R² are both bromo, R³ is —NHR^(3b), andR^(3b) is C₁₋₆ alkyl. R^(3b) can be, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,branched pentyl, n-hexyl, or branched hexyl. In some embodiments, R^(3b)is methyl.

In some embodiments, R¹ and R² are both chloro. In some embodiments, R¹and R² are both chloro, and R³ is —OH.

In some embodiment, R¹ and R² are both chloro, R³ is —NHR^(3b), andR^(3b) is C₁₋₆ alkyl. R^(3b) can be, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,branched pentyl, n-hexyl, or branched hexyl. In some embodiments, R^(3b)is methyl.

In some embodiments, the invention provides compounds of the structure:

or any pharmaceutically acceptable salt thereof where R¹ and R² are bothhalo (including fluoro, bromo, chloro, or iodo). In some embodiments, R¹and R² are both bromo. In some embodiments, R¹ and R² are both chloro.In some embodiments, R¹ is bromo and R² is chloro. In some embodiments,R¹ is chloro and R₂ is bromo.

While GC-1 was designed as a cardiac-sparing treatment forhypercholesterolemia by activating TRβ in the liver, recent studies havedemonstrated its potential in demyelinating diseases ranging frommultiple sclerosis (Baxi E G et al. Glia 62, 1513-1529 (2014);incorporated by reference herein) to X-linked adrenoleukodystrophy(Hartley, M. D. et al. Endocrinology 158, 1328-1338 (2017); Genin E C etal. J Steroid Biochem Mol Biol 116, 37-43 (2009); both of which areincorporated by reference herein). Despite these promising results, theeffectiveness of GC-1 in treating demyelination is potentially limitedby low brain uptake (Trost et al. 200 supra) and reduced receptoractivation compared to thyroid hormone T3 (i.e., triiodothyronine;(2S)-2-amino-3-[4-(4-hydroxy-3-iodo-phenoxy)-3,5-diiodo-phenyl]propanoicacid). While many of the structural features of GC-1 are critical forits binding affinity and receptor selectivity, Yoshihara et al. 2003supra) the 3,5-dimethyl constituents are not optimal. There is a largebody of structure-activity relationship and quantitativestructure-activity relationship data demonstrating that thyromimeticswith inner ring methyl substitutions have significantly reduced activityin comparison to structurally similar analogs with inner ring halogensubstitutions.

The iodine-free analog 3′-isopropyl-3,5-dibromo-L-thyronine (DIBIT) was2- to 7-fold more potent than L-T4 in rat heart rate elevation andanti-goiter assays (Taylor R E et al. Endocrinology 80, 1143-1147(1967); incorporated by reference herein) while the halogen-free analog3′-isopropyl-3,5-dimethyl-DL-thyronine (DIMIT) had little measurableactivity in the same assays (Jorgensen E C and Wright J, J Med Chem 13,745-747 (1970); incorporated by reference herein). For the TRα-selectivecompounds CO22 and CO24, replacement of inner ring methyl groups withbromines improved binding affinity by 15-fold (Ocasio C A and Scanlan TS, ACS Chem Biol 1, 585-593 (2006) and Ocasio C A and Scanlan T S,Bioorg Med Chem 16, 762-770 (2008); both of which are incorporated byreference herein).

A QSSR study of thyroid hormone analogs suggested a mechanism for thesefindings—inner ring halogens can form a dipole-dipole interaction with abackbone carbonyl in the TR ligand binding domain, which influencesbinding affinity and selectivity (Valadares N F et al. J Chem Inf Model49, 2606-2616 (2009); incorporated by reference herein). These datasuggest that GC-1 could be improved by synthesizing new analogs thatreplace the inner ring methyl groups with halogens.

Replacing the inner ring methyl groups of GC-1 with halogens required anew synthetic approach. Work described in Dabrowski M et al. TetrahedronLetters 46, 4175-4178 (2005), which is incorporated by reference herein,provided a template for producing the necessary4-hydroxy-2,6-dihalobenzaldehyde intermediates by selectivedeprotonation of the 4-position of silyl protected 3,5-dihalophenolswith lithium amide reagents. The method was improved by replacing themethyl ether and trimethylsilyl ether protecting groups used byDabrowski with the more sterically bulky triethylsilyl ether protectinggroup, which significantly improved the selectivity of thedeprotonation. These intermediates were used in a slightly alteredversion of the GC-1 synthesis reported in Placzek A T and Scanlan T S,Tetrahedron 71, 5946-5951 (2015); which is incorporated by referenceherein. The 4-hydroxy-2,6-dihalobenzaldehyde intermediates could not bealkylated with tertbutyl chloroacetate using the standard cesiumcarbonate/DMF conditions due to the halogen substitutions reducing thenucleophilicity of the phenol. However, the reaction went to completionand in good yield after converting the alkyl chloride into an alkyliodide via an in situ Finklestein reaction.

Reagents and Conditions: (a) triethylsilyl chloride, imidazole, DCM, 0°C., 95%; (b) (i) nBuLi, DIA/TMP, THF, −78° C. (ii) DMF, 56-67%; (c)tertchloroacetate, NaI, Cs2CO3, acetone, 60-65° C., 84-88%; (d) NaI,NaOH, NaOCl, MeOH, H₂O, 87% (e) MOMC1, TBAI, NaOH, DCM, H2O, 81%; (f)(i) iPMgCl, THF, 0° C. to RT (ii) 4, −78° C., 54-79%; (g) TFA,triethylsilane, DCM, 0° C. to RT, 58-69%.

After forming the tert-butyl oxyacetate intermediate, the carbon-carbonbond formation proceeded in the same fashion as with GC-1 by forming anarylmagnesium with 7 that attacked the benzaldehyde to form a carbinolintermediate. The arylmagnesium nucleophile will not likely exchangewith aryl chlorides or bromides at cryogenic temperatures and iscompatible with the tert-butyl ester protecting group. Reduction of thecarbinol and deprotection of the tert-butyl ester and methoxymethylether protecting groups proceeded simultaneously with TFA andtriethylsilane in dichloromethane. The dibromo analog JD-20 wassynthesized in 27% overall yield and the dichloro analog JD-21 wassynthesized in 17% yield, both in five steps.

III. Pharmaceutical Compositions

The compounds disclosed herein may be included in pharmaceuticalcompositions (including therapeutic and prophylactic formulations),typically combined together with one or more pharmaceutically acceptablecarriers (known equivalently as vehicles) and, optionally, othertherapeutic ingredients.

Such pharmaceutical compositions can be formulated for administration tosubjects by a variety of mucosal administration modes, including byoral, rectal, intranasal, intrapulmonary, intravitrial, or transdermaldelivery, or by topical delivery to other surfaces including the eye.Optionally, the compositions can be administered by non-mucosal routes,including by intramuscular, subcutaneous, intravenous, intra-arterial,intra-articular, intraperitoneal, intrathecal, intracerebroventricular,or parenteral routes. In other examples, the compound can beadministered ex vivo by direct exposure to cells, tissues or organsoriginating from a subject.

To formulate the pharmaceutical compositions, the compound can becombined with various pharmaceutically acceptable additives. Desiredadditives include, but are not limited to, pH control agents, such asarginine, sodium hydroxide, glycine, hydrochloric acid, citric acid, andthe like. In addition, local anesthetics (for example, benzyl alcohol),isotonizing agents (for example, sodium chloride, mannitol, sorbitol),adsorption inhibitors (for example, Tween®-80), solubility enhancingagents (for example, cyclodextrins and derivatives thereof), stabilizers(for example, serum albumin), and reducing agents (for example,glutathione) can be included.

When the composition is a liquid, the tonicity of the formulation, asmeasured with reference to the tonicity of 0.9% (w/v) physiologicalsaline solution taken as unity, is typically adjusted to a value atwhich no substantial, irreversible tissue damage will be induced at thesite of administration. Generally, the tonicity of the solution isadjusted to a value of about 0.3 to about 3.0, such as about 0.5 toabout 2.0, or about 0.8 to about 1.7. The compound can be dispersed inany pharmaceutically acceptable carrier, which can include a hydrophiliccompound having a capacity to disperse the compound, and any desiredadditives. The carrier can be selected from a wide range of suitablecompounds, including but not limited to, copolymers of polycarboxylicacids or salts thereof, carboxylic anhydrides (for example, maleicanhydride) with other monomers (for example, methyl (meth)acrylate,acrylic acid and the like), hydrophilic vinyl polymers, such aspolyvinyl acetate, polyvinyl alcohol, polyvinylpyrrolidone, cellulosederivatives, such as hydroxymethylcellulose, hydroxypropylcellulose andthe like, and natural polymers, such as chitosan, collagen, sodiumalginate, gelatin, hyaluronic acid, and nontoxic metal salts thereof.Often, a biodegradable polymer is selected as a carrier, for example,polylactic acid, poly(lactic acid-glycolic acid) copolymer,polyhydroxybutyric acid, poly(hydroxybutyric acidglycolic acid)copolymer and mixtures thereof.

Alternatively or additionally, synthetic fatty acid esters such aspolyglycerin fatty acid esters, sucrose fatty acid esters and the likecan be employed as carriers. Hydrophilic polymers and other vehicles canbe used alone or in combination, and enhanced structural integrity canbe imparted to the vehicle by partial crystallization, ionic bonding,cross-linking and the like. The carrier can be provided in a variety offorms, including fluid or viscous solutions, gels, pastes, powders,microspheres, and films for direct application to a mucosal surface.

The compound can be combined with the carrier according to a variety ofmethods, and release of the compound can be by diffusion, disintegrationof the vehicle, or associated formation of water channels. In somecircumstances, the compound is dispersed in microcapsules (microspheres)or nanoparticles prepared from a suitable polymer, for example,5-isobutyl 2-cyanoacrylate (see, for example, Michael et al. J. PharmacyPharmacol. 43, 1-5, (1991), and dispersed in a biocompatible dispersingmedium, which yields sustained delivery and biological activity over aprotracted time.

Pharmaceutical compositions for administering the compound can also beformulated as a solution, microemulsion, or other ordered structuresuitable for high concentration of active ingredients. The vehicle canbe a solvent or dispersion medium containing, for example, water,ethanol, polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycol, and the like), and suitable mixtures thereof.Proper fluidity for solutions can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of a desired particlesize in the case of dispersible formulations, and by the use ofsurfactants. In many cases, it will be desirable to include isotonicagents, for example, sugars, polyalcohols, such as mannitol andsorbitol, or sodium chloride in the composition. Prolonged absorption ofthe compound can be brought about by including in the composition anagent which delays absorption, for example, monostearate salts andgelatin.

In certain embodiments, the compound can be administered in a timerelease formulation, for example in a composition which includes a slowrelease polymer. These compositions can be prepared with vehicles thatwill protect against rapid release, for example a controlled releasevehicle such as a polymer, microencapsulated delivery system orbioadhesive gel. Prolonged delivery in various compositions of thedisclosure can be brought about by including in the composition agentsthat delay absorption, for example, aluminum monostearate hydrogels andgelatin. When controlled release formulations are desired, controlledrelease binders suitable for use in accordance with the disclosureinclude any biocompatible controlled release material which is inert tothe active agent and which is capable of incorporating the compoundand/or other biologically active agent. Numerous such materials areknown in the art. Useful controlled-release binders are materials thatare metabolized slowly under physiological conditions following theirdelivery (for example, at a mucosal surface, or in the presence ofbodily fluids). Appropriate binders include, but are not limited to,biocompatible polymers and copolymers well known in the art for use insustained release formulations. Such biocompatible compounds arenon-toxic and inert to surrounding tissues, and do not triggersignificant adverse side effects, such as nasal irritation, immuneresponse, inflammation, or the like. They are metabolized into metabolicproducts that are also biocompatible and easily eliminated from thebody.

Exemplary polymeric materials for use in the present disclosure include,but are not limited to, polymeric matrices derived from copolymeric andhomopolymeric polyesters having hydrolyzable ester linkages. A number ofthese are known in the art to be biodegradable and to lead todegradation products having no or low toxicity. Exemplary polymersinclude polyglycolic acids and polylactic acids, poly(DL-lacticacidco-glycolic acid), poly(D-lactic acid-co-glycolic acid), andpoly(L-lactic acid-coglycolic acid). Other useful biodegradable orbioerodable polymers include, but are not limited to, such polymers aspoly(epsilon-caprolactone), poly(epsilon-aprolactone-CO-lactic acid),poly(epsilon.-aprolactone-CO-glycolic acid), poly(betahydroxy butyricacid), poly(alkyl-2-cyanoacrilate), hydrogels, such as poly(hydroxyethylmethacrylate), polyamides, poly(amino acids) (for example, L-leucine,glutamic acid, L-aspartic acid and the like), poly(ester urea),poly(2-hydroxyethyl DL-aspartamide), polyacetal polymers,polyorthoesters, polycarbonate, polymaleamides, polysaccharides, andcopolymers thereof. Many methods for preparing such formulations arewell known to those skilled in the art (see, for example, Sustained andControlled Release Drug Delivery Systems, J. R. Robinson, ed., MarcelDekker, Inc., New York, 1978). Other useful formulations includecontrolled-release microcapsules (U.S. Pat. Nos. 4,652,441 and4,917,893), lactic acid-glycolic acid copolymers useful in makingmicrocapsules and other formulations (U.S. Pat. Nos. 4,677,191 and4,728,721) and sustained-release compositions for water-soluble peptides(U.S. Pat. No. 4,675,189).

The pharmaceutical compositions of the disclosure typically are sterileand stable under conditions of manufacture, storage and use. Sterilesolutions can be prepared by incorporating the compound in the requiredamount in an appropriate solvent with one or a combination ofingredients enumerated herein, as required, followed by filteredsterilization. Generally, dispersions are prepared by incorporating thecompound and/or other biologically active agent into a sterile vehiclethat contains a basic dispersion medium and the required otheringredients from those enumerated herein. In the case of sterilepowders, methods of preparation include vacuum drying and freeze-dryingwhich yields a powder of the compound plus any additional desiredingredient from a previously sterile-filtered solution thereof. Theprevention of the action of microorganisms can be accomplished byvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

IV. Methods for Treating Neurogenerative Disorders

Disclosed herein are methods of treating a subject with aneurodegenerative disorder through administration of one or more of thedisclosed compounds. The compounds can be administered by anyappropriate route including orally, parenterally, or topically. Inparticular examples, sobetirome, or a pharmaceutically acceptable saltthereof, is administered orally. In certain examples, sobetirome, or apharmaceutically acceptable salt thereof, is administered parenterally.In some embodiments, sobetirome, or a pharmaceutically acceptable saltthereof, is administered buccally, sublingually, sublabially, or byinhalation. In other embodiments, sobetirome, or a pharmaceuticallyacceptable salt thereof, is administered sublingually. In yet otherembodiments, sobetirome, or a pharmaceutically acceptable salt thereof,is administered parenterally. In particular embodiments, sobetirome, ora pharmaceutically acceptable salt thereof, is administeredintra-arterially, intravenously, intraventricularly, intramuscularly,subcutaneously, intraspinally, intraorbitally, intracranially orintrathecally.

The administration of a pharmaceutical composition comprising thedisclosed compounds can be for prophylactic or therapeutic purposes. Forprophylactic and therapeutic purposes, the treatments can beadministered to the subject in a single bolus delivery, via continuousdelivery (for example, continuous transdermal, mucosal or intravenousdelivery) over an extended time period, or in a repeated administrationprotocol (for example, by an hourly, daily or weekly, repeatedadministration protocol). The therapeutically effective dosage of thetreatments for viral infection can be provided as repeated doses withina prolonged prophylaxis or treatment regimen that will yield clinicallysignificant results to alleviate one or more symptoms or detectableconditions associated with a neurodegenerative disorder.

An effective amount or concentration of the disclosed compounds may beany amount of a composition that alone, or together with one or moreadditional therapeutic agents, is sufficient to achieve a desired effectin a subject. The effective amount of the agent will be dependent onseveral factors, including, but not limited to, the subject beingtreated and the manner of administration of the therapeutic composition.In one example, a therapeutically effective amount or concentration isone that is sufficient to prevent advancement, delay progression, or tocause regression of a disease, or which is capable of reducing symptomscaused by any disease, including neurodegenerative disorders.

In one example, a desired effect is to reduce or inhibit one or moresymptoms associated with a neurodegenerative disorder. The one or moresymptoms do not have to be completely eliminated for the composition tobe effective. For example, a composition can decrease the sign orsymptom by a desired amount, for example by at least 20%, at least 50%,at least 80%, at least 90%, at least 95%, at least 98%, or even at least100%, as compared to how the sign or symptom would have progressed inthe absence of the composition or in comparison to currently availabletreatments.

The actual effective amount will vary according to factors such as thetype of neurological disorder to be protected against/therapeuticallytreated and the particular status of the subject (for example, thesubject's age, size, fitness, extent of symptoms, susceptibilityfactors, and the like) time and route of administration, other drugs ortreatments being administered concurrently, as well as the specificpharmacology of treatments for viral infection for eliciting the desiredactivity or biological response in the subject. Dosage regimens can beadjusted to provide an optimum prophylactic or therapeutic response.

An effective amount is also one in which any toxic or detrimental sideeffects of the compound and/or other biologically active agent isoutweighed in clinical terms by therapeutically beneficial effects. Anon-limiting range for a therapeutically effective amount of treatmentsfor viral infection within the methods and formulations of thedisclosure is about 0.0001 μg/kg body weight to about 10 mg/kg bodyweight per dose, such as about 0.0001 μg/kg body weight to about 0.001μg/kg body weight per dose, about 0.001 μg/kg body weight to about 0.01μg/kg body weight per dose, about 0.01 μg/kg body weight to about 0.1μg/kg body weight per dose, about 0.1 μg/kg body weight to about 10μg/kg body weight per dose, about 1 μg/kg body weight to about 100 μg/kgbody weight per dose, about 100 μg/kg body weight to about 500 μg/kgbody weight per dose, about 500 μg/kg body weight per dose to about 1000μg/kg body weight per dose, or about 1.0 mg/kg body weight to about 10mg/kg body weight per dose.

Determination of effective amount is typically based on animal modelstudies followed up by human clinical trials and is guided byadministration protocols that significantly reduce the occurrence orseverity of targeted disease symptoms or conditions in the subject.Suitable models in this regard include, for example, murine, rat,porcine, feline, non-human primate, and other accepted animal modelsubjects known in the art, including the EAE model of multiplesclerosis. Using such models, only ordinary calculations and adjustmentsare required to determine an appropriate concentration and dose toadminister a therapeutically effective amount of the treatments forviral infection (for example, amounts that are effective to alleviateone or more symptoms of a neurodegenerative disorder).

V. Examples

The following examples are for illustration only. In light of thisdisclosure, those of skill in the art will recognize that variations ofthese examples and other examples of the disclosed invention be possiblewithout undue experimentation.

Example 1. Materials and Methods

Transactivation Assay. Human epithelial kidney cells (HEK 293) weregrown to 80% confluency in Dubelcco's modified Eagles 4.5 g/L glucosemedium (high glucose DMEM) containing 10% fetal bovine serum, 50units/mL penicillin and 50 μg/mL streptomycin. The cells weretrypsinized with 0.25% trypsin, then diluted to 5×10⁵ cells/mL with highglucose DMEM. Cells were added to Costar 3917 96-well plates at 5×10⁴cells/well, then incubated at 37° C. for 24 hours. 1.5 μg of TRexpression vector (full length TRα-CMV or TRβ-CMV), 1.5 μg of a reporterplasmid containing a DR4 thyroid hormone response element (TRE) directrepeat spaced by four nucleotides (AGGTCAcaggAGGTCA) cloned upstream ofa minimal thymidine kinase promoter linked to a firefly luciferasecoding sequence, and 0.75 μg of a pRL-SV40 constitutive Renillaluciferase reporter plasmid were diluted into 540 μl of OptiMEM. 27 μLof lipofectamine reagent was diluted into 540 μL of OptiMEM. The plasmidand lipofectamine dilutions were combined then incubated at RT for 10min. The mixture was then diluted into 4.29 mL of OptiMEM. Plates werewashed with 100 μL of phosphate buffered saline (PBS) at pH 7.2 withoutmagnesium or calcium chloride per well. Transfection mixtures were addedat 50 μL per well, then incubated at 37° C. for 4 hours. ModifiedDME/F-12 Ham's medium without phenol red containing 15 mM HEPES andbicarbonate, 5 mM L-glutamine, charcoal-stripped FBS, 50 units/mLpenicillin and 50 μg/mL streptomycin was added at 50 μL per well, thenthe plates were incubated at 37° C. for 20 hours. Drug stocks were madeat 10 mM in DMSO, then serially diluted to 1× concentrations in DME/F-12Ham's. Plates were washed with 100 μL of PBS (pH 7.2) per well. 100 μLof each drug stock was added to the wells in triplicate, and then theplates were incubated at 37° C. for 24 hours.

Cells were assayed for luciferase activity using the Promega DualGlokit. 50 μl of Luciferase Reagent were added per well, the plate wasrocked for 15 min at RT, and then the plate was read for fireflyluciferase activity. A 50 μl volume of Stop & Glo Reagent was added perwell, then the plate was read for Renilla luciferase activity. Datanormalized to Renilla internal control were analyzed with GraphPad Prismv.4a using the sigmoid dose response model to generate EC₅₀ values±SEM.

Animal Studies.

Experimental protocols were in compliance with the National Institutesof Health Guide for the Care and Use of Laboratory Animals and approvedby the Oregon Health & Science University Institutional Animal Care &Use Committee. Wild type male C57BL/6J mice, aged 8-10 weeks, werehoused in a climate controlled room with a 12 hour light-dark cycle withad libitum access to food and water.

Distribution Studies.

Mice were injected once intraperitoneally (ip) with GC-1 at 9.14μmol/kg, and analogs at 0.914, 9.14, and 30.5 μmol/kg. Euthanasia wasperformed on three mice per dose at 1 hr and the tissues and blood wereharvested. Tissues were immediately frozen and blood was kept on ice fora minimum of 30 minutes and then spun down at 7,500×G for 15 minutes.Serum (100 uL) was collected and was stored with tissues at −80° C.until samples were processed.

Serum Processing.

The serum samples were warmed to RT and 10 uL of 2.99 μM internalstandard (D6-GC-1) was added to them. Acetonitrile (500 uL) was addedand the sample was vortexed for 20 seconds. The sample was thencentrifuged at 10,000×G for 15 minutes at 4° C. Next, 90% of the uppersupernatant was transferred to a glass test tube and concentrated usinga speedvac for 1.5 hr at 45° C. The dried sample was then dissolved in400 μL of 50:50 ACN:H2O and vortexed for 20 seconds. The resultingmixture was transferred to an Eppendorf tube and centrifuged at 10,000×Gfor 15 minutes. The supernatant was filtered with 0.22 04 centrifugalfilters and submitted for LCMS/MS analysis. The standard curve was madewith 100 μL of serum from a 8-10 week old mouse not injected with T3,GC-1, or analogs. The processing was performed exactly the same exceptafter filtering the sample was split among 6 vials. GC-1, JD-20, andJD-21 were added to 5 of the 6 vials to make final concentrations ofeach compound in matrix of (0.1 pg/μL, 1 pg/μL, 10 pg/μL, 100 pg/μL, and1000 pg/μL).

Brain Processing.

The brain samples were warmed to RT and transferred to a homogenizertube with 5 GoldSpec ⅛ chrome steel balls (Applied IndustrialTechnologies). The resulting tube was weighed and then 1 mL of H2O wasadded, followed by 10 μL, of 2.99 μM internal standard (D6-Sobetirome).The tube was homogenized with a Bead Bug for 30 seconds and thentransferred to a Falcon® tube containing 3 mL of ACN. A 1 ml volume ofACN was used to wash the homogenizer tube. Then the solution wastransferred back to the Falcon® tube. The sample was then processedusing the same method for the serum processing described above exceptthe sample was concentrated in a glass tube using a speed vac for 4 hrat 45° C.

Gene Activation.

Mice were injected once intraperitoneally (ip) with vehicle (1:1saline/DMSO), T3 at 0.305 μmol/kg, GC-1 at 9.14 μmol/kg, and analogs at0.914, 9.14, and 30.5 μmol/kg. Euthanasia was performed on three miceper dose at 2 hr and the tissues were harvested. The brain tissuescollected for qPCR analysis were processed according to a protocol forRNA extraction using Trizol reagent and the PureLink RNA mini kit, usingQiagen RNase-free DNase kit during the optional DNase treatment step. 1μg of extracted RNA was used to synthesize cDNA via a reversetranscription (RT) reaction using the Qiagen QuantiTect ReverseTranscription kit. DNA contamination was controlled for by duplicatingone sample without the addition of RT enzyme. Expression of the Hairless(Hr) gene was measured by QPCR using the QuantiTect SYBR green PCR kitfrom Qiagen. The primer sequences for hairless (Fwd:CCAAGTCTGGGCCAAGTTTG; Rev: TGTCCTTGGTCCGATTGGAA) were previouslydescribed by Barca-Mayo19. The template cDNA was diluted 2-fold tominimize the interference of RT reagents in the qPCR reaction.Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) was the housekeepinggene used for normalizing between samples. Data analysis for single doseexperiment was done using the comparative CT method to look at therelative differences in Hr gene expression. Data analysis fordose-response experiment was done using GraphPad Prism v.4a with thesigmoid dose response model to generate EC₅₀ values±SEM.

Chemistry General.

¹H NMR were taken on a Bruker 400. All ¹H NMR were calibrated to the NMRsolvent reference peak (D6-acetone, CDCl3). Anhydrous tetrahydrofuran(THF) and dimethylformamide (DMF) were obtained from a Seca SolventSystem. All other solvents used were purchased from Sigma-Aldrich orFisher. Purity analysis of final compounds was determined to be >95% byHPLC. HPLC analysis was performed on a Varian ProStar HPLC with anAgilent Eclipse Plus C18 5 μM column (4.6×250 mm) with a gradient of 10%to 95% acetonitrile (0.1% TFA) over 15 minutes.

Example 2. Preparation of (3,5-Dibromophenoxy)Triethylsilane (2a)

1a (5.04 g, 20 mmol) and imidazole (4.09 g, 60 mmol) were dissolved in80 mL of DCM. The solution was cooled to 0° C., then triethylsilylchloride (5.03 mL, 30 mmol) was added, then the reaction was stirred at0° C. for 30 min. The reaction was diluted with 160 mL of Et2O, washed2× with 50 mL of H2O and 2× with 50 mL of brine, then dried with MgSO₄,filtered, and concentrated to give the 2a in quantitative yield, whichwas used without purification. ¹H NMR (400 MHz, CDCl3): δ 7.37 (t, 1H),7.10 (d, 2H), 1.02 (t, 9H), 0.82 (q, 6H).

Example 3. Preparation of 4-Hydroxy-2,6-Dibromobenzaldehyde (3a)

A flask was loaded with molecular sieves, then flame-dried under vacuum.After cooling under argon, 2a (5.49 g, 15 mmol) was loaded, then theflask was sealed, evacuated, and flushed with argon. 30 mL of dry THFwere added and degassed, then the solution was cooled to −78° C. Asecond flask was loaded with molecular sieves, then flame-dried undervacuum. After cooling under argon, diisopropylamine (4.6 mL, 33 mmol)was added, followed by 60 mL of dry THF, then the solution was degassedand cooled to −78° C. 2.5 M n-butyllithium solution in hexanes (12 mL,30 mmol) was added, then the solution was stirred for 1 hr at −78° C.The lithium diisopropylamide solution was transferred dropwise viacannula to the 2a solution, then the deprotonation was stirred for 1 hrat −78° C. 5.8 mL of dry DMF (75 mmol) were added, then the reaction wasstirred for 1 hr at −78° C. The reaction was decanted into 50 mL of 1 Naqueous HCl. The aqueous layer was extracted 3× with 90 mL of Et₂O. Theorganic fractions were combined, washed 2× with 50 mL of brine, thendried with MgSO₄, filtered, and concentrated to give the crude product,which was precipitated from hexanes at −78° C. to give 2.8 g of 3a (67%yield). ¹H NMR (400 MHz, d6-acetone) δ 10.16 (s, 1H), 7.27 (s, 2H).

Example 4. Preparation of Tert-Butyl2-(3,5-Dibromo-4-Formylphenoxy)Acetate (4a)

3a (2.8 g, 10 mmol), sodium iodide (3 g, 20 mmol), and cesium carbonate(3.24 g, 10 mmol) were dissolved in 40 mL of acetone. 2.86 mL tert-butylchloroacetate (20 mmol) were added, then the reaction was refluxed at65° C. for 2 hr. The reaction was diluted with 80 mL of Et₂O, washed 2×with 30 mL of water and 2× with 30 mL of brine, then dried with MgSO₄,filtered, and concentrated. The product was precipitated from hexanesand collected by filtration, then dried under vacuum to give 3.49 g of4a (88% yield). ¹H NMR (400 MHz, CDCl₃) δ 10.23 (s, 1H), 7.19 (s, 2H),4.59 (s, 2H), 1.52 (s, 9H).

Example 5. Preparation of (3,5-Dichlorophenoxy)Triethylsilane (2b)

1b (6.54 g, 40 mmol) and imidazole (8.18 g, 120 mmol) were dissolved in160 mL of DCM. The solution was cooled to 0° C., then triethylsilylchloride (10 mL, 60 mmol) was added, then the reaction was stirred at 0°C. for 30 min. The reaction was diluted with 320 mL of Et₂O, washed 2×with 100 mL of H2O and 2× with 75 mL of brine, then dried with MgSO₄,filtered, and concentrated to give 2b, which was used withoutpurification and weighed 10.58 g after drying (95% yield). ¹H NMR (400MHz, CDCl₃) δ 6.98 (t, 1H), 6.76 (d, 2H), 1.02 (t, 9H), 0.77 (q, 6H).

Example 6. Preparation of 4-Hydroxy-2,6-Dichlorobenzaldehyde (3b)

A flask was loaded with molecular sieves, then flame-dried under vacuum.After cooling under argon, 2b (3.6 g, 13 mmol) was loaded, then theflask was sealed, evacuated, and flushed with argon. 13 mL of dry THFwere added and degassed, then the solution was cooled to −78° C. Asecond flask was loaded with molecular sieves, then flame-dried undervacuum. After cooling under argon, 2,2,6,6-tetramethylpiperdidine (1.84g, 13 mmol) was added, followed by 13 mL of dry THF, then the solutionwas degassed and cooled to −78° C. 2.5 M n-butyllithium solution inhexanes (5.2 mL, 13 mmol) was added, then the solution was stirred for20 min at 0° C. The lithium TMP solution was transferred dropwise viacannula to the 2b solution, then the deprotonation was stirred for 30min at −78° C. 5 mL of dry DMF (65 mmol) were added, then the reactionwas stirred for 30 min at −78° C. The reaction was decanted into 15 mLof 1 N aqueous HCl. The aqueous layer was extracted 3× with 15 mL ofEtOAc. The organic fractions were combined, washed 2× with 15 mL ofbrine, then dried with MgSO4, filtered, and concentrated to give thecrude product, which was recrystallized from hexanes at −20° C. to give1.39 g of 3b (56% yield). ¹H NMR (400 MHz, d6-acetone) δ 10.37 (s, 1H),7.01 (s, 2H).

Example 7. Preparation of Tert-Butyl2-(3,5-Dichloro-4-Formylphenoxy)Acetate (4b)

3b (1.15 g, 6 mmol), sodium iodide (1.8 g, 12 mmol), and cesiumcarbonate (1.94 g, 6 mmol) were dissolved in 24 mL of acetone. 1.72 mLtert-butyl chloroacetate (12 mmol) were added, then the reaction wasrefluxed at 60° C. for 24 hr. The reaction was diluted with 30 mL ofEt₂O, washed 2× with 10 mL of water and 2× with 10 mL of brine, thendried with MgSO4, filtered, and concentrated. The crude oil wasredissolved in a minimal amount of Et₂O then added dropwise to 100 mL ofvigorously stirring hexanes at −78° C. The precipitate was collected byfiltration and dried under vacuum to give 1.545 g of 4b (84% yield). ¹HNMR (400 MHz, CDCl₃) δ 10.43 (s, 1H), 6.92 (s, 2H), 4.59 (s, 2H), 1.52(s, 9H).

Example 8. Preparation of 4-Iodo-2-Isopropylphenol (6)

5 (6.8 g, 50 mmol) and NaI (7.5 g, 50 mmol) were dissolved in 70 mL ofMeOH. 10 M aqueous NaOH (5 mL, 50 mmol) was added, then the solution wascooled to 0° C. 6.25% w/v aqueous NaOCl (62.5 mL, 50 mmol) was addeddrop wise over 24 hr at 0° C. The reaction was acidified to pH 7 with 12N aqueous HCl, then quenched with 10 mL of saturated aqueous Na₂S₂O₃.The aqueous layer was extracted 3× with Et₂O. The organic fractions werecombined, washed 2× with brine, then dried with MgSO₄, filtered, andconcentrated to give the crude product, which was purified by flashchromatography (silica gel, hexane/ethyl acetate, 1-20%) to give 11.35 gof 6 (87% yield) as a reddish oil. ¹H NMR (400 MHz, CDCl3) δ 7.47 (d,1H), 7.36 (dd, 1H), 6.54 (d, 1H), 3.16 (m, 1H), 1.25 (d, 6H).

Example 9. Preparation of 4-Iodo-2-Isopropyl-1-(Methoxymethoxy)Benzene(7)

6 (2.62 g, 10 mmol) and tetrabutylammonium iodide (369 mg, 1 mmol) weredissolved in 100 mL of DCM. 10 mL of 10 M aqueous NaOH were added,followed by 5 mL of 6 M chloromethyl methyl ether in MeOAc. The reactionwas stirred for 30 min at RT, then diluted with 200 mL of Et₂O. Theorganic layer was washed 2× with 100 mL of H₂O and 2× with 100 mL ofbrine, then dried with MgSO₄, filtered, and concentrated to give thecrude product, which was purified by flash chromatography (silica gel,hexane/ethyl acetate, 1-20%) to give 2.48 g of 7 (81% yield). ¹H NMR(400 MHz, CDCl3) δ 7.47 (d, 1H), 7.42 (dd, 1H), 6.83 (d, 1H), 5.18 (s,2H), 3.47 (s, 3H), 3.27 (m, 1H), 1.20 (d, 6H).

Example 10. Preparation of Tert-Butyl2-(3,5-Dibromo-4-(Hydroxy(3-Isopropyl-4-(Methoxymethoxy)Phenyl)Methyl)Phenoxy)Acetate (8a)

A flask was loaded with 4 Å molecular sieves and flame-dried undervacuum. 7 (1.47 g, 4.8 mmol) was loaded and the flask was sealed,evacuated, and flushed with argon. 24 mL of dry THF were added anddegassed, then the solution was cooled to 0° C. Isopropylmagnesiumchloride (2 M THF, 5.5 mL, 7.2 mmol) was added, then the reaction wasstirred for 2 hours at RT. A second flask was loaded with 4 Å molecularsieves and flame-dried under vacuum. 4a (946 mg, 2.4 mmol) was loadedand the flask was sealed, evacuated, and flushed with argon. 12 mL ofdry THF were added and degassed. The arylmagnesium solution was cooledto −78° C., then the 4a solution was added drop wise via cannula and thereaction was stirred for 1 hour at −78° C. The reaction was quenchedwith 10 mL of 1 N aqueous HCl. The aqueous layer was extracted 3× with10 mL of EtOAc. The organic fractions were combined and washed 2× with10 mL of brine. The organic layer was dried with MgSO₄, filtered, andconcentrated to give the crude product, which was purified by flashchromatography (silica gel, hexanes/EtOAc 4-40%) to give 1.089 g of 8a(79% yield). ¹H NMR (400 MHz, CDCl3) δ 7.24 (d, 1H), 7.17 (s, 2H), 7.00(d, 1H), 6.90 (dd, 1H), 6.51 (d, 1H), 5.21 (s, 2H), 4.53 (s, 2H), 3.49(s, 3H), 3.34 (m, 3H), 1.52 (s, 9H), 1.21 (t, 6H).

Example 11. Preparation of2-(3,5-Cibromo-4-((3-Isopropyl-4-Hydroxyphenyl)Methyl)-Phenoxy)AceticAcid (9a)

8a (1.089 g, 1.9 mmol) was dissolved in 19 mL of DCM with 1.21 mL oftriethylsilane (7.58 mmol). The solution was cooled to 0° C., then 4.35mL of trifluoroacetic acid (56.9 mmol) were added and the reaction wasstirred for 30 min at 0° C., then 2 hr at RT. Solvent was removed undervacuum, then the product was precipitated by the addition of hexanes andcollected by filtration. The solid was dried under vacuum to give 505 mgof JD-20 (9a) (58% yield). ¹H NMR (400 MHz, CDCl3) δ 7.19 (s, 2H), 7.10(d, 1H), 6.82 (dd, 1H), 6.64 (d, 1H), 4.68 (s, 2H), 4.28 (s, 2H), 3.18(m, 1H), 1.24 (d, 6H).

Example 12. Preparation of Tert-Butyl2-(3,5-Dichloro-4-(Hydroxy(3-Isopropyl-4-(Methoxymethoxy)Phenyl)Methyl)Phenoxy)Acetate (8b)

A flask was loaded with 4 Å molecular sieves and flame-dried undervacuum. 7 (459 mg, 1.5 mmol) was loaded and the flask was sealed,evacuated, and flushed with argon. 6 mL of dry THF were added anddegassed, then the solution was cooled to 0° C. Isopropylmagnesiumchloride (2 M THF, 1.125 mL, 2.25 mmol) was added, then the reaction wasstirred for 2 hours at RT. A second flask was loaded with 4 Å molecularsieves and flame-dried under vacuum. 4b (305 mg, 1 mmol) was loaded andthe flask was sealed, evacuated, and flushed with argon. 4 mL of dry THFwere added and degassed. The arylmagnesium solution was cooled to −78°C., then the 4b solution was added drop wise via cannula and thereaction was stirred for 1 hour at −78° C. The reaction was quenchedwith 5 mL of 1 N aqueous HCl. The aqueous layer was extracted 3× with 5mL of EtOAc. The organic fractions were combined and washed 2× with 5 mLof brine. The organic layer was dried with MgSO₄, filtered, andconcentrated to give the crude product, which was purified by flashchromatography (silica gel, hexanes/EtOAc 2-20%) to give 260 mg of 8b(54% yield). ¹H NMR (400 MHZ, CDCl3) δ 7.26 (d, 1H), 6.99 (dd, 1H), 6.94(d, 1H), 6.93 (s, 2H), 6.50 (d, 1H), 5.21 (s, 2H), 4.53 (s, 2H), 3.50(s, 3H), 3.33 (m, 1H), 3.23 (d, 1H), 1.52 (s, 9H), 1.21 (t, 6H).

Example 13. Preparation of2-(3,5-Dichloro-4-((3-Isopropyl-4-Hydroxyphenyl)Methyl)-Phenoxy)AceticAcid (9b)

8b (260 mg, 0.54 mmol) was dissolved in 5.4 mL of DCM with 0.345 mL oftriethylsilane (2.16 mmol). The solution was cooled to 0° C., then 1.24mL of trifluoroacetic acid (16.2 mmol) were added and the reaction wasstirred for 30 min at 0° C., then 2 hr at RT. Solvent was removed undervacuum, then the product was precipitated by the addition of hexanes andcollected by filtration. The solid was dried under vacuum to give 137 mgof JD-21 (9b) (69% yield). ¹H NMR (400 MHz, CDCl3) δ 7.12 (d, 1H), 6.95(s, 2H), 6.86 (dd, 1H), 6.64 (d, 1H), 4.68 (s, 2H), 4.18 (s, 2H), 3.17(m, 1H), 1.24 (d, 6H).

Example 14. Biological Activity of Halogenated Compounds

Cell-based in vitro transactivation assays show that JD-20 and JD-21have improved potency in comparison to their parent GC-1 (FIG. 1). Whileincreases in potency at TRα were modest, greater improvements were seenat TRβ, nearly matching the EC50 of T3 (Table 1).

TABLE 1 Subtype selectivity measured from EC50 values from TRE-drivendual luciferase transactivation assays. Compound EC₅₀ TRα (nM) EC₅₀ TRβ(nM) TRβ/TRα T3 1.01 ± 0.4  1.49 ± 1.57 0.678 GC-1 74.7 ± 28.9 2.82 ±1.81 26.5 JD-20 7.96 ± 6.95 0.88 ± 1.12 9.04 JD-21 7.82 ± 3.61 1.24 ±1.30 6.31

A distribution study was carried out in C57BL/6J mice to determine theconcentrations in brain and serum after systemic (ip) administration.Mice were given single 9.14 μNmol/kg doses of GC-1, JD-20, or JD-21.Tissue and blood were collected 1 hr post-injection and theconcentration of the drugs was determined by LC-MS/MS analysis (FIG. 2).JD-21 showed roughly comparable brain uptake compared to GC-1 whileJD-20 was somewhat lower. The serum levels of JD-20 and JD-21 were bothsignificantly lower than GC-1, combining to give JD-21 a higher brain:serum ratio than GC-1 while JD-20 had a brain: serum ratio comparable toGC-1.

Induction of Hairless (Hr), a TR target gene, mRNA expression in thebrain was determined by qPCR and normalized to glyceraldehyde3-phosphate dehydrogenase (GAPDH) mRNA (FIG. 3). Vehicle (1:1saline/DMSO) was used as a negative control and saturating doses of T3(0.305 μmol/kg) and GC-1 (9.14 μmol/kg) were used as positive controls.JD-21 at 9.14 μmol/kg (2.4-fold) had significantly (p<0.05) greaterinduction of Hr expression in comparison to GC-1 at 9.14 μmol/kg(1.6-fold). JD-20 and JD-21 at 0.914 μmol/kg had comparable Hr inductionto GC-1 at the same dose, suggesting roughly 10-fold greater potencythan GC-1.

The EC₅₀ values of Hr mRNA induction in the brain normalized to GAPDHmRNA expression by GC-1, JD-20, and JD-21 (FIG. 4) were determined usingthe same experimental protocol. The EC50 for GC-1 was 8.20±12.65μmol/kg, the EC50 for JD-20 was 1.49±1.08 μmol/kg, and the EC50 forJD-21 was 1.21±1.75 μmol/kg, making the halogenated analogs roughly6-fold more potent than GC-1 at inducing Hr mRNA expression in thebrain.

While GC-1 has become one of the standard TRβ-selective thyromimetics inthe field, this study makes clear that replacing the inner ring methylgroups with a halogen produces significantly improved compounds thatmaintain critical properties of the parent. The TRβ-selectivity and CNSpenetration of GC-1 are preserved in JD-20 and JD-21, suggesting thatthey should be effective in CNS indications.

The improved potency of JD-20 and JD-21 is consistent with numerousthyromimetic SAR studies that have found superior activity for analogswith halogens in the 3,5-position compared to similar analogs withmethyl groups at those positions. What is surprising in this instance isthat by most measures JD-20 and JD-21 appear to have very similarproperties. In previous thyromimetic SAR studies changing halogensfrequently produced dramatic changes in both potency and selectivity. Onthis scaffold the only major difference is found in brain uptake, whereJD-20 has a reduced uptake in comparison to GC-1 and JD-21.

Example 15. Preparation of 2-(3,5-dibromo-4-(4-hydroxy-3-isopropylbenzyl) phenoxy)-N-methylacetamide(MA-JD20, 10a)

2-(3,5-dibromo-4-(4-hydroxy-3-isopropylbenzyl) phenoxy) acetic acid (100mg, 0.22 mmol) was dissolved in methanol (4 mL) in a sealed tube and onedrop of concentrated sulfuric acid was added to it. The sealed reactionmixture was heated to 65° C. with stirring for one hour. It was thencooled to room temperature and TLC (ethyl acetate: hexane 1:1) showedcomplete conversion to the corresponding methyl ester. To this solutionwas then added 40% methyl amine in water (285 μl, 3.3 mmol, 15 equiv.)and it was again heated to 65° C. for one hour in sealed condition. Itwas cooled and complete conversion to the product was observed by TLC.Sodium hydroxide (0.5N, 10 ml) was added to it and the product wasextracted with dichloromethane (3×50 ml). The organic layers werecombined, dried on anhydrous Mg₂SO₄, filtered and concentrated. Thecrude product was purified by flash chromatography (50% hexane in ethylacetate). On recrystallization from a mixture of hexane anddichloromethane, the final compound was obtained (70 mg, 0.15 mmol,68%). ¹H NMR (400 MHz, MeOH-d₄): δ=7.35 (s, 2H), 6.98 (d, 1H, J=2.3 Hz),6.74 (dd, 1H, J=8.3 Hz, 2.3 Hz), 6.62 (d, 1H, J=8.2 Hz), 4.55 (s, 2H),4.26 (s, 2H), 3.24 (septet, 1H, J=6.9 Hz), 2.84 (s, 3H), 1.17 (d, 6H,J=6.98 Hz). HRMS exact mass calculated for C₁₉H₂₁Br₂NO₃[M+H] ⁺: m/z471.99416, found m/z 471.99446.

Example 16. Preparation of 2-(3,5-dichloro-4-(4-hydroxy-3-isopropylbenzyl) phenoxy)-N-methylacetamide(MA-JD21, 10b)

2-(3, 5-dichloro-4-(4-hydroxy-3-isopropylbenzyl) phenoxy) acetic acid(100 mg, 0.27 mmol, 1 equiv.) was dissolved in methanol (5 mL) in asealed tube. Sulfuric acid (1 drop) added to it and the reaction wassealed and heated to 65° C. for one hour while stirring. It was cooledto room temperature and TLC analysis (ethyl acetate: hexane 1:1) showscomplete conversion to the intermediate methyl ester. To this was thenadded 40% methyl amine in water (320 μl, 4 mmol, 15 equiv.). Thereaction is resealed and heated to 65° C. for one hour. The reactionflask was cooled to room temperature and sodium hydroxide (0.5N, 10 mL)added to it. The reaction product was extracted with dichoromethane(3×50 mL). The organic layers were combined, dried on anhydrous Mg₂SO₄,filtered and concentrated. Purification by flash chromatography (50%hexane in ethylacetate) gave the product as a white solid (65 mg, 0.17mmol, 63%). ¹H NMR (400 MHz, MeOH-d₄): δ=7.12 (s, 2H), 7.01 (d, 1H,J=1.98 Hz), 6.77 (dd, 1H, J=8.21 Hz, 2.26 Hz), 6.62 (d, 1H, J=8.21 Hz),4.56 (s, 2H), 4.15 (s, 2H), 3.23 (septet, 1H, J=7.14 Hz), 2.85 (s, 3H),1.17 (d, 6H, J=6.93 Hz). HRMS exact mass calculated for C₁₉H₂₁Cl₂NO₃[M+H] ⁺: m/z 384.09455, found m/z 384.09473.

Example 17. Biological Activity of Halogenated Amides

Animal Studies.

Wild type male C57Bl/6 mice, aged 8-10 weeks, were housed in aclimate-controlled room with a 12 hour light-dark cycle with ad libitumaccess to food and water. To compare the single time-point drugdistribution of JD-20 with JD-20 generated from the amide MA-JD20, andJD-21 with JD-21 generated from the amide MA-JD-21, the concentrationsof the parent drugs were analyzed in brain and serum of mice byadministering a dose of 3.05 μmol/kg (three mice per dose) with JD-20,JD-21, MA-JD20 and MA-JD21 both intraperitoneally and orally. Thecompounds were dissolved in a mixture of 50:50 DMSO and 0.9% sodiumchloride bacteriostatic solution. Oral gavage was performed with the useof plastic feeding tubes (20 ga×38 mm, Instech Laboratories Inc., PA,USA) connected to 500 μl insulin syringes (Covidien LLC MA, USA). Inboth experiments, the mice were euthanized after 1 hour following drugadministration.

As a follow-up of the single time point study, a 24 h time course studythrough oral gavage was performed for the amides, MA-JD20 and MA-JD21,and the corresponding JD-20 or JD-21 concentrations were measured inbrain and blood of mice. Pharmacokinetic time-course curves weregenerated from these analyses and area under the curve (AUC) values forbrain and blood were obtained.

The tissues were processed as follows: The brains were collected inpreviously weighed homogenizer tubes with 3 Gold Spec ⅛ chrome steelballs (Applied Industrial Technologies) and immediately frozen at −80°C. The blood samples were kept on ice for 30 mins and then spun down at5400×G at 4° C. for 15 min. Serum (100 μl) was collected from the topand stored at −80° C. until the samples were processed.

Serum Processing:

The serum samples were warmed to room temperature. Acetonitrile (500 μl)and the internal standard d₆-sobetirome (2.99 μM, 10 μl) were added toeach sample and vortexed for 20 seconds. They were then centrifuged at10,000×G for 15 minutes at 4° C. The supernatants were transferred to aset of labeled 13×100 mm borosilicate glass tubes and concentrated inthe speedvac concentrator at 45° C. for 2 hours. The dried samples werethen dissolved in 400 μl of a 50:50 mixture of acetonitrile and waterand vortexed for 20 seconds. The resulting mixtures were transferred toEppendorf tubes and centrifuged at 10,000×G for 15 minutes at 4° C. Theserum samples thus prepared were submitted for LC-MS/MS analysis toquantify the amount of free JD-20 or JD-21.

The standard curve was made with 100 μl of serum collected from an 8-10week old C57Bl/6 mouse that received vehicle only (a mixture of 50:50DMSO and 0.9% sodium chloride bacteriostatic solution) injection. Theserum sample was processed exactly the same way except after finalcentrifugation the sample was split into 6 vials. To 5 out of these 6vials was added a mixture of JD-20 and JD-21 to make the concentrationof each compound in matrix of (0.1ρg/μl, 1.0ρg/μl, 10ρg/μl/100ρg/μl and1000ρg/μl).

Brain Processing:

The brain samples were warmed to room temperature and weighed. Water (1ml) and the internal standard d₆-Sobetirome (2.99 μM, 10 μl) were addedto each sample and vortexed for 20 seconds. They are homogenized in OmniBead ruptor 24 for one minute and then transferred to labeled 15 mlFalcon tubes each containing 3 ml of acetonitrile. A 1 ml volume ofacetonitrile was used to wash the homogenizer tube and the washing wasadded to the falcon tube. The tubes were vortexed for 20 seconds andcentrifuged at a speed of 10,000×G for at 4° C. The supernatants fromthese tubes are carefully decanted into a set of labeled 13×100 mmborosilicate glass tubes and concentrated in the speedvac at 45° C. for4 hours. The samples were then processed using the serum processingmethod for LC-MS/MS analysis.

Results.

Both amides MA-JD20 and MA-JD21 delivers more of the parent drugs to theCNS compared to unmodified JD-20 or JD-21 from an equimolar systemicdose of 3.05 μmol/kg, as shown in FIG. 5A.

It was also observed that both amides reduce the peripheral exposure ofthe corresponding parent drug as shown in FIG. 5B. This decreased serumconcentration also supports the fact that these amides considerablyimproved the CNS distribution of the corresponding parent drug. Bycomparing the brain to serum ratios of the amides with the unmodifiedcompounds, it was observed that the amides reduced peripheral exposureof the parent drugs in serum by more than four fold (FIG. 5C). Similarresults were observed with oral administration using the same dose, i.e.3.05 μmol/kg (FIG. 6)

Following the single time point drug distribution evaluation, to furtherunderstand the pharmacokinetic properties of the amide, a 24 htime-course study was conducted by administering an oral dose of 9.14μmol/kg of MA-JD20 to mice. The JD-20 concentrations generated in brainand blood were analyzed and area under the curve (AUC) values for brainand serum were obtained (FIG. 7). The AUC_(brain)/AUC_(serum) ratio foramide MA-JD-20 is observed to be 0.89. The C_(max) and T_(max) seemed tobe around 2 h in the brain tissue whereas in the blood the C_(max) andT_(max) occurred between the initial 30 to 45 min time points. This factsuggests that the hydrolysis rate of the amide is slow once it reachesthe CNS. The results obtained from the single point drug distributionwere confirmed by the AUC analyses.

Having shown that the amides MA-JD20 and MA-JD21 deliver more of theparent drugs to the CNS, both by systemic and oral administration, weevaluated next if the amides upregulate the thyroid responsive Hairless(Hr) gene to a greater extent than the corresponding unmodifiedcompounds. Mice were orally administered a dose of 3.05 μmol/kg (threemice per dose) of JD-20, JD-21, MA-JD20 and MA-JD21 and vehicle (1:1saline/DMSO). The brain tissues collected were processed according to aprotocol for RNA extraction using Trizol reagent and the PureLink RNAmini kit; cDNA was made using the Qiagen QuantiTect ReverseTranscription kit and expression of the Hairless (Hr) gene was measuredby qPCR using the QuantiTect SYBR green PCR kit from Qiagen as describedearlier. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was thehousekeeping gene used for normalizing between samples. Data analysiswas done by using the comparative CT method to monitor the relativedifferences in Hr gene expression. The result is shown in FIG. 8. Thisdata is in agreement with the results obtained from the drugdistribution studies.

Example 18. Halogenated Amides are Substrates for Fatty-Acid AmideHydrolase (FAAH)

Materials. Sobetirome and d₆-sobetirome were synthesized as previouslydescribed. (Placzek and Scanlan. Tetrahedron 2015, 71 (35), 5946-5951).Anandamide was purchased from Cayman (90050). Arachidonic acid waspurchased from Signma (23401). dii-arachidonic acid was purchased fromAvanti (861810E). Solvents were HPLC grade from Fisher. Human FAAH cDNAin a pcDNA4 backbone was kindly provided by Prof. Martin Kaczocha (StonyBrook). A C-terminal FLAG sequence was inserted by PCR using thefollowing primers: 5′-CGCAAATGGGCGGTAGGCGTG (CMV forward) and5′-AGACTCGAGTCACTTGTCGTCATCGTCTTTGTAGTCGGATGACTGCTTTTCAGGG GTCAT. TheKpn1/Xho1 digestion fragment was reinserted back into pcDNA4. Theresulting pcDNA4-FAAH-FLAG construct was confirmed by sequencing.

LC/MS-MS.

Compound quantification was performed by LC-MS/MS as previouslydescribed with modifications (Ferrara, and Scanlan, et al. Biorg. Med.Chem. 2017, 25(10) 2743-2753). Chromatography was performed on aHamiliton PRP-C18 column (5 μm, 2.1×50 mm, 100 Å) fit with a Betabasicprecolumn (Thermo). The gradient mobile phase was delivered at a flowrate of 0.5 mL/min, and consisted of two solvents, A: 10 mM ammoniumformate in water and B: 10 mM ammonium formate in 90% acetonitrile, 10%water. The gradient was as follows: 0-0.5 min, hold 10% B; 0.5-5.1 min,10-98% B; 5.1-7 min, hold 98% B; 7-7.1 min, 98-10% B; 7.1-8 min, hold10%. Analytes were identified in negative mode withmultiple-reaction-monitoring (MRM) primarily using parent ion m/z andthe strongest resulting second transition with energies optimized forthe transitions.

FAAH Activity in Cell Homogenate.

COS-7 cells (ATCC CRL-1651) were cultured in Dulbecco's Modified Eagle'sMedium supplemented with 10% FBS, penicillin (100 units/L), andstreptomycin (100 μg/L). Cells (800,000/well) were seeded into 6-wellplates (Falcon 353046) and left to adhere overnight. Cells weretransfected with pcDNA4-FAAH-FLAG with Lipofectamine 2000 (Invitrogen)according to the manufacturer's protocol. Mock transfection controlswere done with transfection reagent and no DNA. Cells were washed 4-dayspost transfection with cold PBS and scraped into TE buffer (125 mM Tris,1 mM EDTA, pH 9) and sonicated (10 sec, 60 Sonic Dismembrator, Fisher).Cell homogenates were stored at −80° C. and protein concentrations weredetermined by BCA (Pierce). Cell homogenates were diluted into TE buffercontaining 0.1% fatty-acid free BSA (Alfa Aesar). Substrates were addedas 50× stocks in DMSO into 504 aliquots of homogenate to a finalconcentration of 100 μM. Reactions were performed with homogenateprotein at 31.25 μg/mL for 15 min at 37° C. Reactions were quenched with1004 acetonitrile and vortexed for 20 s. Samples were clarified bycentrifuge (10,000 rpm, 15 min, 4° C.). The supernatant is diluted50-fold into 2:1 MeCN:H2O containing 300 nM dii-arachindonic acid and 30nM d₆-sobetirome. Samples were centrifuged again (13,200 rpm, 15 min, 4°C.). Products were quantified by LC/MS-MS with standard curves generatedfrom mock samples. Observed rates are expressed as nmol product per mgprotein homogenate per min.

FIG. 9 shows that amide MA-JD20 and MA-JD21 are substrates forfatty-acid amide hydrolase (FAAH). FAAH was overexpressed in COS-7 cellsas described above and cell homogenate was used to measure observedrates of substrate cleavage compared with the classic endogenous FAAHsubstrate anandamide (AEA). Substrate were all tested at 100 μM.Compared to AEA, the thyromimetic amides MA-GC1 (9-fold), MA-JD20(31-fold), and MA-JD21 (20-fold) show decreased rates. However, thethese decreased observed rates are comparable to other known endogenoussubstrates of FAAH (Boger, et al. Bioorg. Med. Chem. Lett. 2000, 10(23), 2613-2616; Cravat, et al. Proc. Natl. Acad. Sci. U S. A. 2001, 98(16), 9371-6) and the halogenated derivatives are close to the activityof the sobetirome amide. Observed rates are expressed as nmol productper mg homogenate protein per min.

Although the foregoing has been described in some detail by way ofillustration and example for purposes of clarity and understanding, oneof skill in the art will appreciate that certain changes andmodifications can be practiced within the scope of the appended claims.In addition, each reference provided herein is incorporated by referencein its entirety to the same extent as if each reference was individuallyincorporated by reference.

What is claimed is:
 1. A method of treating a neurodegenerativedisorder, the method comprising administering an effective amount of acompound of Formula (I):

or a pharmaceutically acceptable salt thereof, to a subject in needthereof, thereby treating the neurodegenerative disorder, wherein R¹ andR² are both chloro, R³ is —NHR^(3b) and R^(3b) is methyl.
 2. The methodof claim 1, wherein the neurodegenerative disorder is a demyelinatingdisease.
 3. The method of claim 1, where the neurodegenerative disorderis X-linked adrenoleukodystrophy.
 4. A unit dosage form comprising acompound of Formula (I):

wherein: R¹ and R² are independently fluoro, chloro, bromo, or iodo; R³is —OH or —NR^(3a)R^(3b); R^(3a) is hydrogen or C₁₋₆ alkyl; and R^(3b)is C₁₋₆ alkyl; or a pharmaceutically acceptable salt thereof.
 5. Theunit dosage form of claim 4, wherein R¹ and R² are independently chloroor bromo, or a pharmaceutically acceptable salt thereof.
 6. The unitdosage form of claim 4, wherein R¹ and R² are both bromo, or apharmaceutically acceptable salt thereof.
 7. The unit dosage form ofclaim 6, wherein R³ is OH, and the compound has the following structure:

a pharmaceutically acceptable salt thereof.
 8. The unit dosage form ofclaim 7, wherein the compound is in the form of the free acid.
 9. Theunit dosage form of claim 8, wherein the unit dosage form is a tablet orcapsule.
 10. The unit dosage form of claim 6, wherein R³ is —NHR^(3b)and R^(3b) is C₁₋₆ alkyl, or a pharmaceutically acceptable salt thereof.11. The unit dosage form of claim 10, wherein R^(3b) is methyl, and thecompound has the following structure:

or a pharmaceutically acceptable salt thereof.
 12. The unit dosage formof claim 11, wherein the compound is in the form of the free base. 13.The unit dosage form of claim 12, wherein the unit dosage form is atablet or capsule.
 14. The unit dosage form of claim 4, wherein R¹ andR² are both chloro, or a pharmaceutically acceptable salt thereof. 15.The unit dosage form of claim 14, wherein R³ is —OH, and the compoundhas the following structure:

a pharmaceutically acceptable salt thereof.
 16. The unit dosage form ofclaim 15, wherein the compound is in the form of the free acid.
 17. Theunit dosage form of claim 16, wherein the unit dosage form is a tabletor capsule.
 18. The unit dosage form of claim 14, wherein R³ is—NHR^(3b) and R^(3b) is C₁₋₆ alkyl, or a pharmaceutically acceptablesalt thereof.
 19. The unit dosage form of claim 18, wherein R^(3b) ismethyl, and the compound has the following structure:

or a pharmaceutically acceptable salt thereof.
 20. The unit dosage formof claim 19, wherein the compound is in the form of the free base. 21.The unit dosage form of claim 20, wherein the unit dosage form is atablet or capsule.
 22. A method of treating a neurodegenerativedisorder, the method comprising administering to a subject in needthereof an effective amount of a unit dosage form of claim
 4. 23. Themethod of claim 22, wherein the neurodegenerative disorder is ademyelinating disease.
 24. The method of claim 22, wherein theneurodegenerative disorder is X-linked adrenoleukodystrophy.
 25. Themethod of claim 22, wherein the neurodegenerative disorder is multiplesclerosis.